The Journal of Physiology ain .Kostrominova Y. Tatiana 1 Ramaswamy S. Krishnan rats old very muscles and skeletal mice in dystrophic impaired of is force of transmission Lateral Physiol J eia col n the and School, Medical C eatet fBoeia Engineering, Biomedical of Departments 01TeAtos ora compilation Journal Authors. The 2011 8. 21)p 1195–1208 pp (2011) 589.5 D,etno iiou longus. digitorum extensor EDL, 7732C [email protected] School, Email: Medical Abbreviations Michigan USA. of 48109-0622, MI University Arbor, Physiology, Ann Integrative St, [email protected] Catherine and Email: E Molecular 1301 USA. MSII, of 48109-2002, Department MI Arbor, Michele: Ann E. Place, Pitcher D. Zina 109 BSRB, 2035 School, Medical and humans dystrophic In matrix. extracellular the to cytoskeleton fibre Abstract sarcomere to lead DGC the injury. of contraction-induced disruptions and and force instability of transmission lateral the were for intact essential the muscles an is muscles, which DGC skeletal of in in contractions rats, during forces that old conclude We severely. impaired very of transmitted were forces laterally and the transmission mice disrupted, was dystrophic fibres lateral of of (DGC) muscles complex and glycoprotein that skeletal dystrophin-associated for longitudinal demonstrated contrast, then rats In We different. muscles forces. and not parallel-fibred of mice whole, transmission of wild-type lateral surface the for the of to measurements attached permitted that and developed mammals, was in phenomenon apparatus this demonstrate To ‘yoke’ loss. no a or little with surface muscle the to laterally summary Non-technical Rsbitd1 oebr21;acpe fe eiin4Jnay21;fis ulse nie1 aur 2011) January 10 online published first 2011; January authors 4 Corresponding revision after accepted 2010; November 17 (Resubmitted now We (WT force. wild-type lateral young in of of measurement demonstrated muscles epimysium the in the enabled been surface to and that not tendons attached report muscle the that has the between developed midway force to was muscles apparatus of fibre of ‘yoke’ activated transmission unique fibres. A an lateral muscle muscles. from to but mammalian laterally damage attenuation, severe force without causing of DGC occurs transmission the muscles, of frog structure the In disrupt gene dystrophin the marltrltasiso ffrecuigisaiiyadicesdssetblt ffirsto fibres of susceptibility increased and In instability decrement. causing without injury. force function DGC contraction-induced and of structure the DGC transmission through in disruptions lateral fibre animals, old impair to mice very or WT fibre dystrophic young of from muscles of in laterally contrast, muscles transmitted skeletal are by developed rats forces and contractions, during that conclude for We contrast, In decrement. both no of or little showed of laterally muscles transmitted forces forces, longitudinal 5 mdx colo ieilg,a h nvriyo ihgn n ro,Mcia 80-20 USA 48109-2200, Michigan Arbor, Ann Michigan, of University the at Kinesiology, of School h ytohngyorti ope DC rvdsa seta ikfo h muscle the from link essential an provides (DGC) complex dystrophin–glycoprotein The mdx T,atro iils G,dsrpi-soitdgyorti ope;EM xrclua matrix; extracellular ECM, complex; glycoprotein dystrophin-associated DGC, tibialis; anterior ATB, ieadvr l assoe ao eutosi h xrsino dystrophin. of expression the in reductions major showed rats old very and mice 3 ieadvr l as ocstasitdltrlywr mardsvrl.Muscles severely. impaired were laterally transmitted forces rats, old very and mice 1 ailE Michele E. Daniel , akL Palmer L. Mark , C .A alnr eateto oeua n nertv hsooy nvriyo Michigan of University Physiology, Integrative and Molecular of Department Faulkner: A. J. 01TePyilgclSceyDI 10.1113/jphysiol.2010.201921 DOI: Society Physiological The 2011 2 ugr,Scino lsi Surgery, Plastic of Section Surgery, h oc eeoe yasnl bei rgmslsi transmitted is muscles frog in fibre single a by developed force The 1 , 5 3 akH a e Meulen der van H. Jack , , 4 n onA Faulkner A. John and ) ieadrt,cmae vrawd ag of range wide a over compared rats, and mice 3 oeua n nertv hsooy and Physiology, Integrative and Molecular 1 2 , 3 ,AbigailRenoux mdx ie uain in mutations mice, 3 , 4 nenlMdcn nthe in Medicine Internal 1195 1196 K. S. Ramaswamy and others J Physiol 589.5
Introduction skeletal muscles lack the DGC, even repeated isometric contractions cause a severe contraction-induced injury A major breakthrough occurred in the understanding of (Claflin & Brooks, 2008) and lengthening contractions muscle mechanics when Street (1983) provided the first cause an injury that is even more severe (DelloRusso physiological evidence that confirmed, in experiments on et al. 2001; Li et al. 2006). The conclusion that in vitro semitendinosus muscles of frogs, that two pathways dystrophin and the DGC protect skeletal muscle fibres of force transmission existed, one longitudinal and the from contraction-induced injury is supported by the other lateral. These experiments demonstrated for the protection from contraction-induced injury provided the first time that most, if not all of the force developed skeletal muscles of dystrophic mice through the expression by a single muscle fibre longitudinally was transmitted of a mini-dystrophin fusion gene that restored dystrophin laterally through the adjacent extracellular matrix (ECM) expression and DGC function in skeletal muscles (Li et al. and muscle fibres to the epimysium of the skeletal muscle. 2006). Despite this early demonstration of the existence of the Unlike muscular dystrophy, with a single underlying lateral transmission of force in skeletal muscles of frogs, cause arising from the loss of dystrophin, the age-related the inability to perform similar experiments on any changes in skeletal muscles arise from multiple underlying mammalian skeletal muscle resulted in a complete lack causes that are largely unknown. The age-related structural of direct evidence that this phenomenon also occurred and functional deficits that have been demonstrated in in the skeletal muscles of mammalian species. Although skeletal muscles of mice (Brooks & Faulkner, 1988), rats no measurements have been made that demonstrate (Larsson et al. 1991) and humans (Dedrick & Clarkson, lateral transmission of force in mammalian muscles, many 1990; Frontera et al. 1991; Ploutz-Snyder et al. 2001) investigators (Pardo et al. 1983; Ervasti & Campbell, 1993; include a loss of motor units (Doherty et al. 1993); muscle Worton, 1995; Rybakova et al. 2000; Paul et al. 2002; atrophy; fatigability and weakness (Young et al. 1984, 1985; Bloch & Gonzalez-Serratos, 2003; Campbell & Stull, 2003; Brooks & Faulkner, 1988; Frontera et al. 1991); a decrease Ervasti, 2003; Huijing, 2003; Bloch et al. 2004; Abmayr & in maximum and sustained power (Faulkner et al. 2008); Chamberlain, 2006; Anastasi et al. 2008; Claflin & Brooks, and an increased susceptibility to contraction-induced 2008) have assumed that the lateral transmission of force injury (Dedrick & Clarkson, 1990; DelloRusso et al. 2001; must function as effectively in mammalian muscles, as Ploutz-Snyder et al. 2001; Li et al. 2006). The possibility evidenced in the muscles of frogs (Street, 1983), despite that during the ageing of mammalian skeletal muscles, theabsenceofanydirectevidencethatsuchisthecase. the loss of dystrophin expression leads to an impaired The pathway proposed by these investigators for lateral transmission of force has not been investigated pre- the lateral transmission of force has focused primarily viously. Here we demonstrate for the first time that force is on the potential of costameres, first described by transferred laterally without decrement in skeletal muscles Pardo and colleagues (1983), to provide the necessary of young wild-type (WT) mice and rats. In contrast, in linkage for the transfer of force laterally from the skeletal muscles of both mdx mice and very old rats, z-discs of skeletal muscle fibres to the ECM (Ervasti, the lateral transmission of force is impaired severely. 2003; Bloch et al. 2004). Within striated skeletal Throughout the manuscript the terms WT, mdx and very muscle fibres, the dystrophin-associated glycoprotein old muscles will be used when appropriate, rather than complex (DGC), situated primarily within costameres, designating the species. The observations on WT, mdx and appears to provide the necessary connection between very old muscles suggest that disruptions associated with the force-generating structures, the sarcomeres, laterally muscular dystrophy, or acquired disruptions of the DGC through the sarcolemma and basement membrane into associated with ageing, may interfere with the mechanical the ECM that is shared with the surrounding muscle connections between skeletal muscle fibres and the ECM fibres (Ervasti & Campbell, 1991; Worton, 1995; Henry & and that such disruptions may lead to impairments in the Campbell, 1996; Bloch & Gonzalez-Serratos, 2003; Ervasti, lateral transmission of force and the subsequent muscle 2003; Michele & Campbell, 2003; Bloch et al. 2004; Lapidos dysfunctions that are associated with both dystrophy and et al. 2004; Anastasi et al. 2008). During contractions, ageing. these potential pathways for the lateral transmission of forces provide the possibility of stabilizing the lengths of sarcomeres that vary in their capability of developing Methods force (Macpherson et al. 1997; Panchangam et al. 2008). The DGC appears to be essential in mammalian skeletal To investigate the effect of the lack of dystrophin on muscles, since a loss of its components causes muscular the lateral transmission of force, adult (12–15 months of dystrophy in both humans (Hoffman et al. 1987; Worton, age) WT (n = 6) and mdx (n = 6) male mice from the 1995; Bloch et al. 2004) and mice (Rybakova et al. C57BL/10ScSn-mdx/J strain were purchased from The 2000; Li et al. 2006). In dystrophic (mdx)mice,whose Jackson Laboratory (Bar Harbor, ME, USA). In addition,